Hydroxylases as therapeutic targets in inflammatory bowel disease
Hydroxylases as therapeutic targets in inflammatory bowel disease
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DOI：
10.1038/labinvest.2013.9
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发表时间：
2013-04-01
影响因子：
5
通讯作者：
Taylor, Cormac T.
中科院分区：
文献类型：
--
作者：
Cummins, Eoin P.;Doherty, Glen A.;Taylor, Cormac T.
炎症性肠病(IBD)是一种常见的临床疾病，包括溃疡性结肠炎和克罗恩病。IBD发生于肠粘膜不适当的免疫活动导致上皮屏障功能障碍，从而导致粘膜免疫系统暴露于管腔抗原物质。这反过来导致炎症循环和进一步的屏障功能障碍，这是疾病发展的基础。尽管在过去的十年中取得了显著的治疗进展，但由于一些患者缺乏治疗反应和不良反应，包括感染和恶性肿瘤风险增加，目前对IBD的免疫抑制和抗炎治疗仍有很大局限性。最近利用IBD实验模型进行的研究发现，细胞内羟基酶是一组负责氧气感知和激活对低氧的适应性转录反应的酶，可能代表IBD治疗的一类新靶点。羟基酶抑制剂在改善结肠炎症状方面是有效的，至少部分是通过促进肠上皮屏障功能。这种保护的机制是由于低氧敏感的转录因子的激活，包括缺氧诱导因子(HIF)和核因子kappaB(NF-kappa B)，它们激活了特定的上皮屏障保护转录程序。本文就小分子羟化酶抑制剂治疗肠易激综合征的作用机制(S)及其治疗潜力作一综述。实验室调查(2013年)93,378-383；doi：10.1038/Labinvest.2013.9；2013年2月18日在线发布
Inflammatory bowel disease (IBD) is a common and debilitating clinical disorder comprising ulcerative colitis and Crohn's disease. IBD occurs when inappropriate immunological activity in the intestinal mucosa results in epithelial barrier dysfunction leading to exposure of the mucosal immune system to luminal antigenic material. This in turn results in the cycles of inflammation and further barrier dysfunction which underlie disease progression. Although significant therapeutic advances have been made over the last decade, current immunosuppressive and anti-inflammatory treatments for IBD have significant limitations due to lack of treatment response in some patients and adverse effects, including increased risk of infection and malignancy. Recent studies using experimental models of IBD have identified that intracellular hydroxylases, a group of enzymes responsible for oxygen sensing and activation of adaptive transcriptional responses to hypoxia may represent a new class of therapeutic targets in IBD. Hydroxylase inhibitors are effective in ameliorating symptoms of colitis at least in part through the promotion of intestinal epithelial barrier function. The mechanism of this protection is due to activation of hypoxia-sensitive transcription factors, including the hypoxiainducible factor (HIF) and nuclear factor kappa-B (NF-kappa B), which activate specific epithelial barrier-protective transcriptional programs. In this review, the mechanism(s) of action and the therapeutic potential of small molecule hydroxylase inhibitors for the treatment of IBD will be discussed. Laboratory Investigation (2013) 93, 378-383; doi:10.1038/labinvest.2013.9; published online 18 February 2013